The goal of this application is to design functional biomaterials to carry antisense plasmids and antisense oligonucleotides to islet beta cell based on results from successful preliminary studies. The designed nontoxic and cationic polymeric carriers are conjugated with a targeting moiety of sulfonylurea (SU) or antiglutamic acid decarboxylase (antiGAD) antibody. These functional and biospecific biomaterials will carry the antisense GAD plasmid to islet beta cells, where they will suppress GAD antigen production and prevent autoimmune induced type I diabetes, which is triggered by GAD antigen. We will construct antisense GAD plasmids containing cDNAs of GAD-65 and GAD-67 with rat insulin promoters for site specific expression of antisense in RNAs. AntiGAD or SU conjugated polyethene glycol (PEG)/polyethylene imine (PEI) copolymer will be synthesized that will form stable complexes with the plasmids. These polymer complexes will target islet beta cells through antigen GAD or SU receptors present in the islet cells, which are expected to enhance transfection and expression. A second approach will also be investigated which includes direct chemical binding of synthesized antisense oligonucleotide (ODN) to SU grafted PEG or antiGAD grafted PEG using an acid labile linkage. A cationic fusogenic oligopeptide, WEAK-LAKA-LAKA-LAKH-LAKA-LKAC-EA (KALA) will be incorporated to form a stable micelle complex with the designed ODN conjugated polymer. This complex traffics to the cell via endocytosis and releases ODN in the acidic endosome by breakdown of the acid labile bond. The use of KALA significantly enhances trancription. After extensive characterization and analysis of in vitro cellular uptake, bioactivity and transfection with the above designed systems, systematic in vivo evaluation will be carried out in NOD mice. Biodistribution, efficacy, duration and optimal dosed delivery will be determined. The obtained results are anticipated to support the proposed application to treat early stage type I diabetes, which currently has no method for treatment.